By Amy Adams, MS

Reviewed By Jeremy Walston, MD and Kristi Silver,  MD
Last Updated September 14, 2000

If you or someone in your family has Type 1 diabetes, you may wonder if other family members are at risk. It turns out that Type 1 diabetes does often run in families. In fact, researchers have found nearly 20 different genes that can affect your risk for developing diabetes.

Two of the best studied genes in Type 1 diabetes are the HLA region and the insulin gene. Although many more Type 1 diabetes genes exist, we will focus on these two because of their central role in the disease. (For recent news about the genetics of Type 1 diabetes, see Related News below.)

The HLA Region

The HLA (human leukocyte antigen) region is a section of a chromosome that contains several genes that are involved in how the immune system works. These genes make proteins that dot the surface of some cells in the immune system. These proteins are important in order for the immune system to distinguish between its own cells and an infectious agent, such as a bacteria or virus. When this system fails, the immune cells attack other cells of the body (such as pancreas cells) in a process called an autoimmune reaction.

There are at least two genes in the HLA region that account for 40 to 50 percent of the diabetes risk that people inherit from their parents. Different versions (or alleles) of these genes can put a person at risk for — or prevent them from — developing Type 1 diabetes. One gene in the HLA region that plays an important role in diabetes is called DR. People can inherit one form of DR from their mother and one form of DR from their father. It's the combination of these two forms of the gene that determine a person's overall risk.

Two forms of DR, designated DR3 and DR4, are present in 95 percent of Type 1 diabetics, and 30 percent have inherited both DR3 and DR4. This is in contrast with the general population, where only 50 percent of people have DR3 or DR4 and 1 to 3 percent have both.

Although both DR3 and DR4 alleles put a person at risk for developing diabetes, the two alleles cause slight differences in the disease:

• Diabetics who have inherited DR3 (but not DR4) develop diabetes at an older age, and tend to have antibodies against pancreatic beta cells but not against insulin. These people are also more likely to develop thyroid autoimmune disease.
• Diabetics who have inherited DR4 (but not DR3) tend to develop diabetes earlier in life and have an immune reaction against insulin.
• Diabetics who inherit both DR3 and DR4 develop diabetes at the youngest age and have the highest levels of antibodies against insulin.

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The Insulin Gene

The insulin gene is the region of DNA that codes for the protein insulin. Changes in DNA near the insulin gene seem to influence a person's susceptibility to diabetes. This region, which is different lengths in different people, determines how much insulin the gene makes. It is composed of a repeated section of DNA called the Variable Number of Tandem Repeats (VNTR). Smaller VNTR regions contain only 26 to 63 DNA repeats, while long regions contain 140 to 200 repeats. If a person inherits two short VNTR regions, they are two to five times more likely to develop Type 1 diabetes than a person with at least one long VNTR.

The longer (protective) VNTR region seems to decrease the amount of insulin produced in the pancreas. This finding may seem contradictory, because the longer VNTR also protects a person from developing diabetes. However, researchers have found that insulin is produced in the thymus during development. (The thymus is also where many cells in the immune system develop). During this time, the longer VNTR causes more insulin to be produced. Researchers think that when developing immune cells are exposed to high levels of insulin, they learn to identify insulin and are less likely to react against it and cause diabetes later in life.

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Genetic Testing

The inheritance patterns of Type 1 diabetes are complicated, with many different genes influencing a person's risk. Because of this array of genes, Type 1 diabetes is not inherited in a clearly dominant or recessive manner. Instead, a person may have one gene that increases their risk (a DR3 or DR4 allele, for example) and other genes that decrease their risk (a long VNTR region). Together, these 20 genes along with environmental factors determine a person's overall risk for developing diabetes.

With so many variables to consider, researchers are still a long way from a genetic test for Type 1 diabetes. Two hurdles to developing a genetic test are:

• Researchers have not yet identified all the gene mutations that put a person at risk for Type 1 diabetes. Even if they did know all of the mutations, researchers find that people with low risk genes (DR2, DR5, or long VNTR regions) can still develop diabetes, so a genetic test might identify people as negative who eventually go on to develop diabetes.
• Even if a genetic test reveals that a person is at high risk, doctors have no course of action for preventing diabetes. Instead, the test may simply add stress to the family and create health insurance problems, while still not improving the person's health.

At this time, knowing a child's genetic risk does not change how doctors treat the disease. For this reason, the American Diabetes Association recommends screening children for diabetes risk (HLA type and the presence of antibodies) only if the child satisfies the following criteria:

• The child has a parent or sibling with Type 1 diabetes.

• The child intends to enter a diabetes prevention study that requires this information.

References

Noble, J. A., et al. (1996). The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am J Hum Genet, 59, 1134-1148.

Dorman, J., et al., (1999). Risk Factors for Insulin-Dependent Diabetes. In (Ed. 2nd), Diabetes in America (pp. 165-178). Bethesda, MD: National Diabetes Data Group, NIH.

Dubois-Laforgue, D., et al. (1997). Insulin-dependent diabetes mellitus in non-DR3/non-DR4 subjects. Hum Immunol, 57, 104-109.

Owerbach, D. and Gabbay, K. H. (1993). Localization of a type I diabetes susceptibility locus to the variable tandem repeat region flanking the insulin gene. Diabetes, 42, 1708-1714.

Bennett, S. T., et al. (1995). Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus [see comments]. Nat Genet, 9, 284-292.